Novel Androstenetriol Interacts with the Mitochondrial Translocator Protein and Controls Steroidogenesis

Midzak, Andrew; Akula, Nagaraju; Lecanu, Laurent; Papadopoulos, Vassilios

doi:10.1074/jbc.m110.203216

Cited by 60 publications

(40 citation statements)

References 68 publications

(87 reference statements)

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“…Other components of the complex include ACBD3 (Acyl-coenzyme A binding domain containing 3) and the regulatory subunit R1α of PKA (62,83,105). TSPO can bind cholesterol through its CRAC domain (106), and mutagenesis in this region interferes with cholesterol binding and transfer of cholesterol into the IMM, preventing steroidogenesis (107). TSPO gene silencing blocks cholesterol transport into the mitochondria, also reducing steroid production, while reintroduction of TSPO is able to restore steroidogenic capacity (83).…”

Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 99%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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Section: Tspo -/-Knockout Mice: New Insights Of An Old Functionmentioning

confidence: 99%

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Gatliff

Campanella

2016

Biochemical Journal

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“…PBR/TSPO ligands stimulate steroid synthesis and promote translocation of cholesterol from OMM to the IMM in several steroidogenic cell types (229)(230)(231). Mutagenesis of the CRAC domain interferes with cholesterol binding and transfer of cholesterol to the IMM ( 228 ), and blocking the binding of cholesterol to the CRAC domain prevents steroidogenesis ( 232 ). Targeted deletion of the TSPO gene in a Leydig cell line blocked cholesterol transport into the mitochondria and reduced steroid production; reintroduction of TSPO into the deficient cell line restored steroidogenic capacity ( 228 ).…”

Section: Structure and Mechanism Of Star's Actionmentioning

confidence: 99%

Early steps in steroidogenesis: intracellular cholesterol trafficking

Miller

Bose

2011

Journal of Lipid Research

429

384

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“…To assess the mechanism of action and specificity by which treatment of primary Leydig cells with TSPO ligands resulted in increased steroid production, young cells were incubated for an initial 30-minute period with 19-Atriol (100 M), which inhibits cholesterol binding at the TSPO CRAC domain (19,41), and then were incubated with 19-Atriol plus LH, Ro5-4864, or FGIN-1-27 for an additional 2 hours. T then was measured by RIA after HPLC separation of steroids.…”

Section: In Vitro Effects Of Tspo Drug Ligands Ro5-4864 and Fgin-1-27mentioning

confidence: 99%

“…Freshly isolated Leydig cells were suspended in M-199 culture media and plated at a density of 3-5 ϫ To determine whether TSPO ligands affected TSPO, Leydig cells were preincubated for 30 minutes with 19-Atriol, a specific inhibitor of the TSPO CRAC domain (39,41), dissolved in dimethylsulfoxide (final concentration in culture medium less than 0.5%), and then further incubated for 2 h with 19-Atriol plus LH, Ro5-4864, or FGIN-1-27. T was measured by RIA after HPLC separation of steroids (42).…”

Section: Effect Of Tspo Drug Ligands On Steroid Production In Vitromentioning

confidence: 99%

Drug Ligand-Induced Activation of Translocator Protein (TSPO) Stimulates Steroid Production by Aged Brown Norway Rat Leydig Cells

et al. 2013

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Translocator protein (TSPO; 18 kDA) is a high-affinity cholesterol-binding protein that is integrally involved in cholesterol transfer from intracellular stores into mitochondria, the rate-determining step in steroid formation. Previous studies have shown that TSPO drug ligands are able to activate steroid production by MA-10 mouse Leydig tumor cells and by mitochondria isolated from steroidogenic cells. We hypothesized herein that the direct, pharmacological activation of TSPO might induce aged Leydig cells, which are characterized by reduced T production, to produce significantly higher levels of T both in vitro and in vivo. To test this, we first examined the in vitro effects of the TSPO selective and structurally distinct drug ligands N,N-dihexyl-2-(4-fluorophenyl)indole-3-acetamide (FGIN-1-27) and benzodiazepine 4Ј-chlorodiazepam (Ro5-4864) on steroidogenesis by Leydig cells isolated from aged (21-24 months old) and young adult (3-6 months old) Brown Norway rats. The ligands stimulated Leydig cell T production significantly, and equivalently, in cells of both ages, an effect that was significantly inhibited by the specific TSPO inhibitor 17,. Additionally, we examined the in vivo effects of administering FGIN-1-27 to young and aged rats. In both cases, serum T levels increased significantly, consistent with the in vitro results. Indeed, serum T levels in aged rats administered FGIN-1-27 were equivalent to T levels in the serum of control young rats. Taken together, these results indicate that although there are reduced amounts of TSPO in aged Leydig cells, its direct activation is able to increase T production. We suggest that this approach might serve as a therapeutic means to increase steroid levels in vivo in cases of primary hypogonadism. (Endocrinology 154: 2156 -2165, 2013)

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Novel Androstenetriol Interacts with the Mitochondrial Translocator Protein and Controls Steroidogenesis

Cited by 60 publications

References 68 publications

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

Early steps in steroidogenesis: intracellular cholesterol trafficking

Drug Ligand-Induced Activation of Translocator Protein (TSPO) Stimulates Steroid Production by Aged Brown Norway Rat Leydig Cells

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